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Developing a safe and effective non-alpha IL-2R agonist to enhance the numbers and activation status of immune effector cells for the treatment of cancer has remained an elusive goal since the initial approval of Interleukin-2 (IL-2). ANV419 comprises an antibody specific for the IL-2Rα-binding domain of IL-2 fused to native hIL-2 and functions as a potent, highly selective, IL-2Rβγ binding agonist. ANV419 has shown high effector selectivity and a favorable safety profile in preclinical testing, including in non-human primates, and is currently being investigated in an ongoing phase I/II dose finding study in multiple tumor types (ANV419-001). Here we present data from the single patient cohort and the initial 3+3 cohort dose escalation. Data cut-off was December 22nd, 2021. Ten patients in five dose cohorts. Patients had progressed melanoma (cutaneous (n=3), uveal (n=2), mucosal (n=1), choroidal (n=1)), renal cell carcinoma(n=1), hepatocellular carcinoma (n=1) and colorectal cancer(n=1) received Q2W doses of ANV419 of 3mcg/kg (n=1), 6mcg/kg (n=1), 12mcg/kg (n=1), 24mcg/kg (n=4) and 48mcg/kg (n=3) body weight without immunosuppressive premedication as a 15-minute intravenous infusion. Patients received a mean of 4 cycles. Minimal follow up of patients completing the dose limiting toxicity (DLT) period is 2 cycles. All patients experienced mild chills (Grade 1) with or without low-grade fever (Grade 1) hours after drug administration. These resolved with antipyretic treatment within hours. There were two grade 2 AEs in two patients related to ANV419. One patient developed Grade 2 CRS (hypotension grade 2 with fever (Grade 1) and chills (Grade 1) that resolved with 500ml intravenous fluid. One patient experienced transient, self-limiting Grade 2 CRS. No drug related Adverse Events >Grade 2 and no DLTs were observed. One patient in the 24 mcg/kg cohort was non evaluable and was subsequently replaced. Pharmacodynamic evaluation on day 4 post-dosing, showed a dose dependent increase of Ki-67 positivity in CD8 T cells (2%, 14%, 37%, 62%, 62% vs. baseline mean (BLM) 2%)) and NK cells (30%, 62%, 75%, 85%, 80% vs BLM 6%) but not CD4 regulatory T cells (4%, 13%, 25%, 16%, 19% vs. BLM 5%) at 3, 6, 12, 24 and 48 mcg/kg doses respectively. Pharmacokinetic data show a dose proportional increase of serum concentration of ANV419. Both PK and PD were conserved over multiple cycles. Four patients continue to receive ANV419. Four patients underwent more than one follow-up imaging, all of which showed stable disease. Updated patient data will be presented during the meeting. ANV419 is very well tolerated and induces a high degree of proliferation in CD8 T cells and NK cells but not Tregs. ANV419-001 will further evaluate the safety and efficacy of ANV419 alone and in combination with other immunotherapy drugs. Citation Format: Elena Garralda, Alonso Guzman, Juanita Lopez, Vicky Sanchez-Perez, Heinz Läubli, Emiliano Calvo, Christoph Huber, Nicole Egli, Aswathy Nair, Julie Mouton, Kirsten Richter, Carlo Lanza, Sangeeta Jethwa, Silvio Costanzo, Christoph Bucher. ANV419, an IL-2R-beta-gamma targeted antibody-IL-2 fusion protein, induces selective effector cell proliferation in patients with progressed cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT140. |
